CN110256196A - The one-pot synthesis method of D, L- body naproxen - Google Patents
The one-pot synthesis method of D, L- body naproxen Download PDFInfo
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- CN110256196A CN110256196A CN201910640213.3A CN201910640213A CN110256196A CN 110256196 A CN110256196 A CN 110256196A CN 201910640213 A CN201910640213 A CN 201910640213A CN 110256196 A CN110256196 A CN 110256196A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
The present invention provides a kind of D, the one-pot synthesis method of L- body naproxen, its spy is being, prepares in accordance with the following steps: (1) dimethylbenzene is added, in the reaction vessel and phenyltrimethyl-ammonium tribromide, 6- methoxyl group -2- propionyl naphthalene react to obtain xylene solution；(2), xylene solution is heated to boiling water removal, then neopentyl glycol and p-methyl benzenesulfonic acid is added in cooling, continues reflux water-dividing reaction after adding；(3), zinc acetate or zinc oxide, temperature rising reflux reaction is added in reaction solution one step up；(4), step is evaporated in the residue that dissolution obtains and sodium hydroxide or potassium hydroxide solution hydrolysis is added upwards, collects aqueous solution and reacts stand-by in next step；(5), Raney's nickel hydrogenation reaction is added in Xiang Shangshu aqueous solution, obtains product.Total recovery reaches 73%, and whole operation one-pot synthesis simplifies technique, environmental-friendly industrialized route.
Description
Technical field
The present invention relates to a kind of D, the one-pot synthesis method of L- body naproxen belongs to organic synthesis field.
Background technique
Naproxen (naproxen) is by syntex public affairs its chemical name is S- (+) -2- (6- methoxy-naphthyl) propionic acid
A kind of non_steroidal anti_inflammatory drug (NSAID) of exploitation is taken charge of, which has stronger anti-inflammatory, antipyretic, analgesic activity.Its anti-inflammatory is made
With more than ten times for phenylbutazone, refrigeration function is 22 times of aspirin, and analgesic activity is 7 times of aspirin.Naproxen tool
Play the role of significantly prostaglandin synthetase being inhibited to reduce the release of prostate, thus play it is antipyretic, analgesia and its it is anti-inflammatory
Effect.It is mainly used for treating rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, various types
Rheumatic myotenositis, the periarthritis of shoulderjoint etc. and the pain as caused by various diseases have good Analgesic And Antipyretic Effects,
And have the advantages that oral absorption is complete, toxicity is low, Small side effects, so naproxen is still the important of antiphlogistic antibacterial field at present
Drug.
D, L- body naproxen be naproxen preparation important intermediate, D, L- body naproxen through fractionation after obtain Nabumetone
It is raw.
D, L- body naproxen chemical name: D, L-2- (6- methoxyl group naphthalene) propionic acid, English name: D, L-2- (6-
methoxynaphtyl)propionic acid
Chemical structural formula:
Molecular formula: C14H14O3
Molecular weight: 230.27, it is off-white color or light yellow crystalline powder.
Study on the synthesis method in relation to naproxen is numerous, as application No. is a kind of D disclosed in 201810431686.8, L- naphthalenes
The preparation method of general life, application No. is a kind of synthesis technologies of DL-naproxen disclosed in 201811405231.5.These reactants
It is low boiling point that toluene, hexamethylene, petroleum ether or n-hexane are selected in system, and reaction efficiency is low, and the reaction time is long, at high cost.
The defects of secondly, that there is also wastewater flow rates is big for existing production technology, total recovery is low, complicated for operation.
Summary of the invention
Present invention seek to address that the technical problems existing in the prior art, especially innovatively propose a kind of D, L- body Nabumetone
Raw one-pot synthesis method, reaction efficiency is high, high income, and wastewater flow rate is few.
In order to realize above-mentioned purpose of the invention, the present invention provides a kind of D, the one pot process sides of L- body naproxen
Method, spy is being, prepares in accordance with the following steps:
(1), dimethylbenzene and phenyltrimethyl-ammonium tribromide are added in the reaction vessel, 6- methoxyl group-is added in stirring and dissolving
Water, stirring layering is added in 2- propionyl naphthalene, reaction to fully reacting after having reacted, upper layer xylene solution is directly entered in next step
Reaction；
(2), the organic phase that step (1) obtains is heated to boiling, then the moisture in removing system is cooled to 60 DEG C -80
DEG C, neopentyl glycol and p-methyl benzenesulfonic acid is added, continues reflux water-dividing reaction after adding, after having reacted, be cooled to 60 DEG C -80 DEG C it is standby
With；
(3), zinc acetate or zinc oxide is added in reaction solution one step up, after temperature rising reflux has reacted, cool to 70 DEG C with
Under, it is added hydrochloric acid solution into system, stirs stratification, during upper organic phase is successively with sodium hydroxide and water washing to pH
Property, it is spare that solvent evaporated obtains residue；
(4), sodium hydroxide or potassium hydroxide solution are added in Xiang Shangshu residue, is heated to reflux hydrolysis, it is cold after having hydrolyzed
But to 50 DEG C hereinafter, with salt acid for adjusting pH 7-8, dimethylbenzene washing collects aqueous solution and reacts stand-by in next step；
(5), above-mentioned aqueous solution is added in autoclave, Raney's nickel is added, hydrogen displacement is heated to boiling, is passed through hydrogen also
Original, filtering after having reacted, after filtrate uses active carbon decoloring, with salt acid for adjusting pH 3-4, Off-white solid is precipitated, and is filtered, drying
Obtain product.
Reaction equation are as follows:
The present invention selects dimethylbenzene as reaction dissolvent, and the boiling point of dimethylbenzene is 137 DEG C -140 DEG C, is heated to boiling reaction
Temperature is high, and reaction efficiency is improved, and the reaction time shortens, and reduces energy consumption, reduces production cost.In the present invention, multiple steps
It does not need to handle, is directly entered the next step, on the one hand make operation simpler, on the other hand reduce post-processing bring waste water
Amount.Entirety yield of the present invention can reach 73% or more, and high income is with high purity.
In step (1), the molar ratio of phenyltrimethyl-ammonium tribromide and 6- methoxyl group -2- propionyl naphthalene is 1.05-1.2:1；
When stirring and dissolving, 35 DEG C -45 DEG C are heated up to, is then cooled to 15-25 DEG C, 6- methoxyl group -2- propionyl naphthalene is added, finishes, in 15-
7-8h is reacted at 25 DEG C to fully reacting.Phenyltrimethyl-ammonium tribromide
In step (2), the molar ratio of the neopentyl glycol and 6- methoxyl group -2- propionyl naphthalene is 0.6-0.8:1, described to first
The molar ratio of benzene sulfonic acid and 6- methoxyl group -2- propionyl naphthalene is 0.1-0.3:1, and the reflux water-dividing reaction time is 3-4h.
In step (3), the molar ratio of zinc acetate or zinc oxide and 6- methoxyl group -2- propionyl naphthalene is 0.1-0.2:1, and reflux is anti-
It is 7-8h between seasonable.The mass concentration of the hydrochloric acid solution is 10%-25%.
In step (4), the mass concentration of sodium hydroxide or potassium hydroxide solution is 25%-35%, sodium hydroxide or hydrogen-oxygen
The molar ratio for changing potassium and 6- methoxyl group -2- propionyl naphthalene is 2.5-3:1.In step (4), the acid is concentrated hydrochloric acid.
In step (5), Hydrogen Vapor Pressure is not less than 3 atmospheric pressure in autoclave.
The additional amount of the Raney's nickel is the 0.01%-0.5% of the Theoretical Mass of hydrolysate.That is the theory of intermediate 5
The 0.01%-0.5% of quality.
The utility model has the advantages that the present invention is raw material by bromo, ketal, rearrangement, hydrolysis, one pot of hydrogenation using 6- methoxy propyl naphthone
Method synthesizes D, L- body naproxen, and total recovery reaches 73%, and intermediate reaction does not need to handle, and is directly entered and reacts in next step, operation
Simply, discharge of wastewater is reduced, it is environmental-friendly.Using dimethylbenzene as solvent, reaction efficiency is improved, shortens the reaction time,
Production cost is reduced, industrialized production is suitble to.
Specific embodiment:
Below with reference to embodiment, invention is further described in detail.
Embodiment 1
1.5 kilograms of dimethylbenzene of the investment in 5L three-necked flask, 600 grams of phenyltrimethyl-ammonium tribromide (1.59mol), 35
DEG C -45 DEG C of stirring and dissolving half an hour.Then it cools to 15 DEG C, is added 320 grams of naphthalene of 6- methoxyl group -2- propionyl (1.5mol),
After the reaction was continued at a temperature of this 8 hours, the stirring liquid separation of 1.5 kg of water is added into system.Upper organic phase is straight without purifying
It taps into reaction in next step.Water phase is collected for recycling phenyltrimethyl-ammonium tribromide.
Previous step xylene solution is poured into 3 liters of three-necked flasks and is heated to boiling, after azeotropic removes system moisture, cools to 60
DEG C 115 grams of neopentyl glycol (1.1mol), 40 grams of p-methyl benzenesulfonic acid (0.23mol) are added.Charging, which finishes, is warming up to reflux, reflux point
Water reacts 4 hours, and HPLC detects raw material and disappears, and cooling down is spare to 60 DEG C, into next step.
20 grams of zinc oxide (0.25mol) is added in xylene solution one step up, temperature rising reflux 8 hours, TLC detection was reacted
It completes, cools to 70 DEG C or less 1000 grams of 10% hydrochloric acid into system, stir stratification, upper organic phase successively uses hydroxide
Sodium and water washing to pH be neutrality.Residue is directly stand-by in next step after rotating dimethylbenzene
25% sodium hydroxide solution 600g is added into above-mentioned residue, is heated to reflux hydrolysis, hydrolysis time is 2h or so,
50 DEG C are cooled to hereinafter, adjusting pH7-8 with concentrated hydrochloric acid.Dimethylbenzene 300g is washed twice, and is collected aqueous solution and is reacted stand-by in next step.
Above-mentioned aqueous solution is added in autoclave, Raney's nickel 2g (theoretical amount of intermediate 5 is 463.74g), hydrogen is added
After displacement 3 times, reduction reaction 2 hours under the hydrogen of 3 atmospheric pressure, filtering is adjusted after filtrate uses active carbon decoloring with hydrochloric acid
PH is 3-4, and Off-white solid is precipitated, and filtering, drying obtains 250 grams of product, purity 98.8%.
Embodiment 2
1.5 kilograms of dimethylbenzene of the investment in 5L three-necked flask, 596 grams of phenyltrimethyl-ammonium tribromide (1.58mol), 35
DEG C -45 DEG C of stirring and dissolving half an hour.Then it cools to 25 DEG C, is added 320 grams of naphthalene of 6- methoxyl group -2- propionyl (1.5mol),
After the reaction was continued at a temperature of this 7 hours, the stirring liquid separation of 1.5 kg of water is added into system.Upper organic phase is straight without purifying
It taps into reaction in next step.
Previous step xylene solution is poured into 3 liters of three-necked flasks and is heated to boiling, after azeotropic removes system moisture, cools to 80
DEG C 125 grams of neopentyl glycol (1.2mol), 78 grams of p-methyl benzenesulfonic acid (0.45mol) are added.Charging, which finishes, is warming up to reflux, reflux point
Water reacts 3 hours, and HPLC detects raw material and disappears, and cooling down is spare to 80 DEG C, into next step.
Zinc acetate 0.15mol is added in xylene solution one step up, temperature rising reflux 7 hours, TLC detection reaction was completed,
Cool to 70 DEG C or less 1000 grams of 25% hydrochloric acid into system, stir stratification, upper organic phase successively use sodium hydroxide and
Water washing is neutral to pH.Residue is directly stand-by in next step after rotating dimethylbenzene
35% potassium hydroxide solution 720g is added into above-mentioned residue, is heated to reflux hydrolysis, hydrolysis time is 2h or so,
50 DEG C are cooled to hereinafter, adjusting pH7-8 with concentrated hydrochloric acid.Dimethylbenzene 300g is washed twice, and is collected aqueous solution and is reacted stand-by in next step.
Above-mentioned aqueous solution is added in autoclave, Raney's nickel 0.046g is added, after hydrogen is replaced 3 times, in 3 atmospheric pressure
Reduction reaction 2 hours under hydrogen, filtering, after filtrate uses active carbon decoloring, adjusting PH with hydrochloric acid is 3-4, and Off-white solid is precipitated,
Filtering, drying obtain 255 grams of naproxen nitration mixture, purity 99.2%.
Embodiment 3
1.5 kilograms of dimethylbenzene of the investment in 5L three-necked flask, 679 grams of phenyltrimethyl-ammonium tribromide (1.8mol), 35 DEG C-
45 DEG C of stirring and dissolving half an hour.Then it cools to 18 DEG C, is added 320 grams of naphthalene of 6- methoxyl group -2- propionyl (1.5mol), this temperature
After the reaction was continued 7 hours under degree, the stirring liquid separation of 1.5 kg of water is added into system.Upper organic phase without purify directly into
Enter in reaction in next step.
Previous step xylene solution is poured into 3 liters of three-necked flasks and is heated to boiling, after azeotropic removes system moisture, cools to 70
DEG C 94 grams of neopentyl glycol (0.9mol), 26 grams of p-methyl benzenesulfonic acid (0.15mol) are added.Charging, which finishes, is warming up to reflux, reflux point
Water reacts 4 hours, and HPLC detects raw material and disappears, and cooling down is spare to 70 DEG C, into next step.
24 grams of zinc oxide (0.3mol) is added in xylene solution one step up, temperature rising reflux 8 hours, TLC detection was reacted
It completes, cools to 70 DEG C or less 1000 grams of 18% hydrochloric acid into system, stir stratification, upper organic phase successively uses hydroxide
Sodium and water washing to pH be neutrality.Residue is directly stand-by in next step after rotating dimethylbenzene
30% sodium hydroxide solution 500g is added into above-mentioned residue, is heated to reflux hydrolysis, hydrolysis time is 2h or so,
50 DEG C are cooled to hereinafter, adjusting pH7-8 with concentrated hydrochloric acid.Dimethylbenzene 300g is washed twice, and is collected aqueous solution and is reacted stand-by in next step.
It is added in autoclave to above-mentioned aqueous solution, Raney's nickel 2.3g is added, after gas displacement 3 times, in the hydrogen of 3 atmospheric pressure
Reduction reaction 2 hours under gas, filtering, after filtrate uses active carbon decoloring, adjusting PH with hydrochloric acid is 3-4, and Off-white solid is precipitated, mistake
Filter, drying obtain 258 grams of naproxen nitration mixture, purity 98.9%.
Claims (9)
1. the one-pot synthesis method of a kind of D, L- body naproxen, spy is being, prepare in accordance with the following steps:
(1), dimethylbenzene and phenyltrimethyl-ammonium tribromide are added in the reaction vessel, 6- methoxyl group -2- third is added in stirring and dissolving
Water is added in naphthone, reaction to fully reacting after having reacted, stirring layering, upper layer xylene solution is directly entered to react in next step；
(2), the organic phase that step (1) obtains is heated to boiling, then the moisture in removing system is cooled to 60 DEG C -80 DEG C, adds
Enter neopentyl glycol and p-methyl benzenesulfonic acid, after adding continue reflux water-dividing reaction, after having reacted, be cooled to 60 DEG C -80 DEG C it is spare；
(3), zinc acetate or zinc oxide is added in reaction solution one step up, after temperature rising reflux has reacted, cool to 70 DEG C hereinafter, to
Hydrochloric acid solution is added in system, stirs stratification, upper organic phase is successively neutral, steaming to pH with sodium hydroxide and water washing
It is spare that dry solvent obtains residue；
(4), sodium hydroxide or potassium hydroxide solution are added in Xiang Shangshu residue, is heated to reflux hydrolysis, is cooled to after having hydrolyzed
50 DEG C hereinafter, adjust pH7-8 with hydrochloric acid, dimethylbenzene washing, collecting aqueous solution, reaction is stand-by in next step；
(5), above-mentioned aqueous solution is added in autoclave, Raney's nickel is added, hydrogen displacement is heated to boiling, is passed through hydrogen reducing, instead
Filtering after having answered after filtrate uses active carbon decoloring, adjusts pH3-4 with hydrochloric acid, and Off-white solid is precipitated, and filtering is dried and produced
Product.
2. the one-pot synthesis method of D according to claim 1, L- body naproxen, spy is being: in step (1), phenyl
The molar ratio of trimethyl tribromide ammonium and 6- methoxyl group -2- propionyl naphthalene is 1.05-1.2:1；When stirring and dissolving, be heated up to 35 DEG C-
It 45 DEG C, is then cooled to 15-25 DEG C, 6- methoxyl group -2- propionyl naphthalene is added, finishes, 7-8h is reacted at 15-25 DEG C to having reacted
Entirely.
3. the one-pot synthesis method of D according to claim 1 or claim 2, L- body naproxen, spy is being: in step (2),
The molar ratio of the neopentyl glycol and 6- methoxyl group -2- propionyl naphthalene is 0.6-0.8:1, the p-methyl benzenesulfonic acid and 6- methoxyl group -
The molar ratio of 2- propionyl naphthalene is 0.1-0.3:1, and the reflux water-dividing reaction time is 3-4h.
4. the one-pot synthesis method of D according to claim 3, L- body naproxen, spy is being: in step (3), acetic acid
The molar ratio of zinc or zinc oxide and 6- methoxyl group -2- propionyl naphthalene is 0.1-0.2:1, reflux time 7-8h.
5. the one-pot synthesis method of D according to claim 4, L- body naproxen, spy is being: described in step (3)
The mass concentration of hydrochloric acid solution is 10%-25%.
6. the one-pot synthesis method of D according to claim 5, L- body naproxen, spy is being: in step (4), hydrogen-oxygen
The mass concentration for changing sodium or potassium hydroxide solution is 25%-35%, sodium hydroxide or potassium hydroxide and 6- methoxyl group -2- propionyl naphthalene
Molar ratio be 2.5-3:1.
7. the one-pot synthesis method of D according to claim 6, L- body naproxen, spy is being: described in step (4)
Acid is concentrated hydrochloric acid.
8. the one-pot synthesis method of D according to claim 7, L- body naproxen, spy is being: in step (5), high pressure
Hydrogen Vapor Pressure is not less than 3 atmospheric pressure in kettle.
9. the one-pot synthesis method of D according to claim 8, L- body naproxen, spy is being: the Raney's nickel adds
Enter the 0.01%-0.5% for the Theoretical Mass that amount is hydrolysate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724700A (en) * | 2021-01-22 | 2021-04-30 | 内蒙古彩晶新材料科技有限公司 | Process for synthesizing permanent violet RL by one-pot method |
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| CN101234963A (en) * | 2008-03-05 | 2008-08-06 | 江苏八巨药业有限公司 | Industrial synthesis technique for DL-naproxen |
| CN108530278A (en) * | 2018-05-08 | 2018-09-14 | 江苏八巨药业有限公司 | A kind of preparation method of D, L- naproxen |
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2019
- 2019-07-16 CN CN201910640213.3A patent/CN110256196A/en active Pending
Patent Citations (2)
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| CN101234963A (en) * | 2008-03-05 | 2008-08-06 | 江苏八巨药业有限公司 | Industrial synthesis technique for DL-naproxen |
| CN108530278A (en) * | 2018-05-08 | 2018-09-14 | 江苏八巨药业有限公司 | A kind of preparation method of D, L- naproxen |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112724700A (en) * | 2021-01-22 | 2021-04-30 | 内蒙古彩晶新材料科技有限公司 | Process for synthesizing permanent violet RL by one-pot method |
| CN112724700B (en) * | 2021-01-22 | 2023-04-07 | 内蒙古彩晶新材料科技有限公司 | Process for synthesizing permanent violet RL by one-pot method |
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